A Study of the Efficacy and Safety of Rituximab in Participants With Systemic Sclerosis

Overview

This study evaluates the efficacy and safety of rituximab compared with placebo in SSc patients. This study consists of a 24-week, double-blind, placebo-controlled period followed by a 24-week active drug treatment period.

Full Title of Study: “Double-Blind, Parallel-group Comparison, Investigators Initiated Phase II Clinical Trial of IDEC-C2B8 (Rituximab) in Patients With Systemic Sclerosis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 9, 2019

Interventions

  • Drug: Double-Blind Placebo
    • The 4-week treatment period (four 375 mg/m2 doses at 1-week intervals) and subsequent 20-week follow-up period constitute one cycle of treatment. In the double-blind period, one cycle of placebo will be administered. In the active drug period, one additional cycle (rituximab) will be administered.
  • Drug: Double-Blind Rituximab
    • The 4-week treatment period (four 375 mg/m2 doses at 1-week intervals) and subsequent 20-week follow-up period constitute one cycle of treatment. In the double-blind period, one cycle of rituximab will be administered. In the active drug period, one additional cycle (rituximab) will be administered.

Arms, Groups and Cohorts

  • Placebo Comparator: Double-Blind Placebo
    • Participants will receive double-blind matching placebo from baseline until week 24. Participants may then receive open-label rituximab from weeks 24 to 48.
  • Experimental: Double-Blind Rituximab
    • Participants will receive double-blind rituximab from baseline until week 24. Participants may then receive open-label rituximab from weeks 24 to 48.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Modified Rodnan Total Skin Thickness Score (mRTSS) during double-blind period
    • Time Frame: From baseline to week 24
    • Absolute change from pre-treatment observation period in skin sclerosis at week 24 of treatment in the double-blind phase, assessed by mRTSS. mRTSS ranging from 0 (normal) to 3 (severe skin thickening) across 17 different body parts. The total score is the sum of the individual skin scores for all these sites, and ranges from 0 to 51 units.

Secondary Measures

  • Change in percent FVC measured in respiratory function test
    • Time Frame: From baseline to week 24
  • Change in percent DLco measured in respiratory function test
    • Time Frame: From baseline to week 24
  • Change in TLC measured in respiratory function test
    • Time Frame: From baseline to week 24
  • Change in serum levels of KL-6
    • Time Frame: From baseline to week 24
  • Change in serum levels of SP-D
    • Time Frame: From baseline to week 24
  • Change in serum levels of SP-A
    • Time Frame: From baseline to week 24
  • Change in percentage of interstitial shadow in lungs by high-resolution computed tomography
    • Time Frame: From baseline to week 24
  • Change in skin thickness measured following biopsy specimen
    • Time Frame: From baseline to week 24
  • Change in HRQOL index measured using MOS 36 Item Short-Form Health Survey
    • Time Frame: From baseline to week 24
  • Change in QOL index of SSc patients, assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI)
    • Time Frame: From baseline to week 24
  • Change in serum antinuclear antibody titers
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-centromere antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-Scl-70 antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-RNA polymerase III antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-ssDNA antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-dsDNA antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-CL antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-β2-GP1 antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of lupus anticoagulant
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-SS-A antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-SS-B antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-cANCA
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-p-ANCA
    • Time Frame: From baseline to week 24
  • Change in serum levels of anti-U1-RNP antibodies
    • Time Frame: From baseline to week 24
  • Change in serum levels of IgG
    • Time Frame: From baseline to week 24
  • Change in serum levels of IgM
    • Time Frame: From baseline to week 24
  • Change in serum levels of IgA
    • Time Frame: From baseline to week 24
  • Change in blood CD19+ B cell count
    • Time Frame: From baseline to week 24
  • Change in blood CD20+ B cell count
    • Time Frame: From baseline to week 24
  • Change in blood CD3+ T cell count
    • Time Frame: From baseline to week 24
  • Expression of human anti-rituximab antibodies
    • Time Frame: From baseline to week 24
  • Overall incidence, severity, causal relationship, and outcome of adverse events
    • Time Frame: From baseline to week 48
  • Incidence of rituximab infusion reactions
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: Area under concentration-time curve from time 0 to final observation (AUC0-t)
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: maximum serum concentration after dosing (Cmax)
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: time to maximum concentration (tmax)
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: terminal half-life (t1/2)
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: mean residence time
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: clearance
    • Time Frame: From baseline to week 48
  • PK profile of rituximab: volume of distribution
    • Time Frame: From baseline to week 48

Participating in This Clinical Trial

Inclusion Criteria

1. Fulfill the diagnostic criteria for systemic sclerosis defined in the 2016 edition of the Clinical Practice Guidelines for Systemic Sclerosis and have an mRTSS of 2 (moderate) or higher for skin sclerosis 2. Aged 20 or older and younger than 80 at the time of consent 3. Have an expected survival of at least 6 months (and expected to allow 6 months of observation) 4. Fulfill the following criteria related to concomitant medications/therapies:

  • Not received corticosteroids equivalent to more than 10 mg/day of prednisolone within 2 weeks before the start of study treatment; and – Not received antifibrotic agents (like nintedanib, pirfenidone, tocilizumab), other investigational products, immunosuppressants (cyclophosphamide, mycophenolate mofetil, ciclosporin, tacrolimus, azathioprine, and mizoribine), high-dose intravenous immunoglobulin, or imatinib 4 weeks prior to the start of study treatment. 5. Provided written consent to participate in the study Exclusion Criteria:

1. Present with pulmonary hypertension* associated with systemic sclerosis *: The patient will undergo echocardiography during the pre-treatment observation period to exclude pulmonary hypertension. The patient will be required to undergo examination by an expert (eg, at the Department of Cardiovascular Medicine) if systolic pulmonary artery pressure exceeds 35 mmHg. 2. Have serious complications (eg, renal crisis) associated with systemic sclerosis (excluding interstitial pneumonia**) **: Patients with interstitial pneumonia will be excluded if the criterion 3) below is met. 3. Have only poor respiratory reserve (%VC or %DLco, both calculated using the "estimation equation more suitable for Japanese," is less than 60% or 40%, respectively) 4. Known to have HIV antibodies 5. Have a positive result for any of the following: HBs antigen, HBs antibody, HBc antibody, and HCV antibody (this criterion does not apply to a positive test for hepatitis B clearly attributable to hepatitis vaccination) 6. Have serious bacterial/fungal infections 7. Have a serious liver disease (AST [GOT] or ALT[GPT] of ≥ 300 IU) 8. Have a serious renal disease (serum creatinine ≥ 2.0 mg/dL) 9. Have severe heart disease 10. Have active tuberculosis 11. Have any known malignancy or a history of malignancy within the past 5 years 12. Have a history of serious infections 13. Have a history of serious hypersensitivity or anaphylactic reactions to any component of rituximab or to mouse proteins 14. Pregnant, postpartum, and lactating women 15. Refuse to practice contraception from the time of consent to at least 12 months after study completion 16. Have any disease or physical/psychiatric conditions that make study participation difficult/inappropriate 17. Received other investigational products within 12 weeks prior to the study treatment or are participating in other clinical research/studies 18. Smoked within 12 weeks prior to the date of consent 19. Is determined by the investigator (or sub-investigator) to be ineligible for the study for any other reason

Gender Eligibility: All

Minimum Age: 20 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Tokyo University
  • Collaborator
    • Japan Agency for Medical Research and Development
  • Provider of Information About this Clinical Study
    • Principal Investigator: Ayumi Yoshizaki, Principal Investigator – Tokyo University
  • Overall Official(s)
    • Ayumi Yoshizaki, MD, PhD, Principal Investigator, Tokyo University

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